Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial

Tardif JC, Ballantyne CM, Barter P, et al., for the Can Hdl Infusions Significantly QUicken Atherosclerosis REgression (CHI-SQUARE) Investigators
Eur Heart J (2014) doi: 10.1093/eurheartj/ehu171. online: April 29, 2014

Background

Epidemiological studies have shown an inverse association between HDL-cholesterol and risk of coronary heart disease complications [1]. In the context of aggressive statin use and very low LDL-c levels, HDL particle number appears to be a better predictor of outcomes [2].
In patients with manifest coronary heart disease, however, this inverse relationship seems to be substantially weakened [3]. Several trials that modify HDL-c levels have yielded disappointing results.
CER-001 is an engineered lipoprotein particle that mimics pre-beta HDL, composed of recombinant human apolipoprotein A-9 and two phospholipids. After i.v. administration, it can rapidly mobilize large quantities of cholesterol into the HDL fraction [4].
This study assessed the safety and efficacy of CER-001 as a series of weekly infusions on coronary atherosclerosis, as assessed by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Patients were randomised to CER-001 or placebo infusions within 14 days of having experienced an acute coronary syndrome. In the double-blind CHI-SQUARE (Can Hdl Infusions Significantly QUicken Atherosclerosis Regression) study, 507 patients received six weekly volume-matched infusions of CER-001 or placebo (3 or 6 or 12 mg/kg CER-001 vs. placebo).

Main results

• Mean total atheroma volume at baseline was 155.24 + 67.99 mm³. The adjusted means for change in total atheroma volume were -2.71, -3.13, -1.50 and -3.05 mm³ in the placebo, CER-001 3, 6, and 12 mg/kg groups respectively. No statistically significant differences were seen with any of the CER-001 doses when compared with placebo.
• The change from baseline to follow-up (3-5 weeks after last infusion) in the coronary artery score, as assessed by QCA, was -0.022, -0.036, -0.022, and -0.015 mm in the placebo and CER-001 3, 6, and 12 mg/kg groups, respectively. The changes with CER-001 were not significantly different from the effect seen with placebo.
• Changes from baseline to follow-up in cumulative coronary stenosis score were -0.51, 2.65, 0.71, and -0.77% in the placebo and CER-001 3, 6, and 12 mg/kg groups respectively. Only the change observed with 3 mg/kg CER-001 was statistically significant vs. placebo (nominal P< 0.01).
• 10 patients (8.3%) in the placebo group experienced at least one major adverse cardiovascular event, as opposed to 16 (13.3%), 17 (13.7%) and 12 (9.8%) in the respective CER-001 groups. The differences were not statistically significant.
• CER-001 was generally well tolerated. Few incidences of infusion-type reactions, drug-related hypersensitivity were seen in the CER-001 groups, as well as treatment-emergent elevations in ALT in all four study groups.
• A post hoc re-analysis of the IVUS recordings by a separate group confirmed that the primary endpoint was not met.

Conclusion

This study showed that none of the tested doses of the HDL-mimetic CER-001 yielded benefit on coronary atherosclerosis, as assessed by IVUS and QCA.
CHI-SQUARE is a larger study than three earlier clinical studies evaluating HDL infusions. None of these studies have demonstrated a therapeutic benefit on coronary atherosclerosis, in patients with a recent acute coronary syndrome.
A dose-related increase in cholesterol mobilisation was seen, which did not translate into progressively greater effects on IVUS, underscoring the lack of predictive value of this biomarker. Other properties of HDL particles may therefore be more relevant.

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References

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